High-intensity interval training alleviates depressive-like behaviors and is associated with differences in gut microbiota composition and prefrontal LPS-associated inflammatory measures in CUMS rats

Abstract

Background Exercise is a safe and effective intervention for improving depressive symptoms, but the effects and related mechanisms of high-intensity interval training (HIIT) remain unclear. Growing evidence suggests that interactions among the gut microbiota, immune-inflammatory responses, and the central nervous system may contribute to the development and progression of depression. This study investigated whether a 4-week HIIT intervention attenuated depressive-like behaviors and explored related differences in gut microbiota composition and prefrontal cortical lipopolysaccharide (LPS)-associated inflammatory measures. Methods Forty male Sprague-Dawley rats were initially assigned to either the chronic unpredictable mild stress (CUMS) or control conditions. Following CUMS modeling and corresponding control procedures, rats were further allocated to four groups: CUMS_Sed, CUMS_Ex, Con_Sed, and Con_Ex. Exercise groups performed HIIT on motorized treadmills. Depressive-like behaviors were assessed using the sucrose preference test and the open field test, and body weight was monitored longitudinally as a secondary physiological outcome during CUMS exposure. Gut microbiota composition was profiled using 16S rRNA gene sequencing. LPS levels in the prefrontal cortex and ileum, and IL-1β levels in the prefrontal cortex, were measured using enzyme-linked immunosorbent assay, and prefrontal cortical Toll-like receptor 4 ( TLR4 ) and Rela (NF-κB p65/RelA) mRNA expression levels were assessed by reverse transcription quantitative PCR. Results CUMS induced marked depressive-like behaviors, including reduced sucrose preference and altered open field test performance. HIIT partially attenuated these behavioral alterations. In exploratory microbiota analyses, HIIT-treated CUMS rats differed from sedentary CUMS rats in gut microbial diversity and taxonomic composition and also showed lower prefrontal cortical LPS and IL-1β levels and lower TLR4 and Rela mRNA expression. In contrast, IL-1β was higher in exercised control rats, and ileal LPS levels were lower overall in exercised rats. Conclusions These findings suggest that HIIT-related improvements in depression-related phenotypes were accompanied by attenuation of LPS-associated inflammatory changes in the prefrontal cortex, while exploratory microbiota analyses identified differences in gut microbiota composition. HIIT may represent a promising exercise-based strategy for improving stress-related depressive-like phenotypes.

The authors' abstract, as published at the source. Frontiers in Cellular and Infection Microbiology, 2026 · DOI ↗